Human Genetics

, Volume 137, Issue 11–12, pp 905–909 | Cite as

Lowry-Wood syndrome: further evidence of association with RNU4ATAC, and correlation between genotype and phenotype

  • Ivan Shelihan
  • Sophie Ehresmann
  • Cinzia Magnani
  • Francesca Forzano
  • Chiara Baldo
  • Nicola Brunetti-Pierri
  • Philippe M. Campeau
Original Investigation


Lowry-Wood syndrome (LWS) is a skeletal dysplasia characterized by multiple epiphyseal dysplasia associated with microcephaly, developmental delay and intellectual disability, and eye involvement. Pathogenic variants in RNU4ATAC, an RNA of the minor spliceosome important for the excision of U12-dependent introns, have been recently associated with LWS. This gene had previously also been associated with microcephalic osteodysplastic primordial dwarfism (MOPD) and Roifman syndrome (RS), two distinct conditions which share with LWS some skeletal and neurological anomalies. We performed exome sequencing in two individuals with Lowry-Wood syndrome. We report RNU4ATAC pathogenic variants in two further patients. Moreover, an analysis of all RNU4ATAC variants reported so far showed that FitCons scores for nucleotides mutated in the more severe MOPD are higher than RS or LWS and that they were more frequently located in the 5′ Stem–Loop of the RNA critical for the formation of the U4/U6.U5 tri-snRNP complex, whereas the variants are more dispersed in the other conditions. We are thus confirming that RNU4ATAC is the gene responsible for LWS and provide a genotype–phenotype correlation analysis.



We thank the families for participating in the study and the Réseau de Médecine Génétique Appliqué du Québec for bioinformatics assistance. We acknowledge support from the Canadian Institutes of Health Research of Canada and the Fonds de Recherche Santé Québec to PMC. We thank the Galliera Genetic Biobank (Galliera Hospital), member of the Telethon Network of Genetic Biobanks (project n.GTB12001), for providing us with DNA sample of second patient. We dedicate the study to the memory of Dr. Giovanni Camera, the radiologist who contributed in reaching a clinical diagnosis for both patients.

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Supplementary material

439_2018_1950_MOESM1_ESM.docx (25 kb)
Supplementary material 1 (DOCX 24 KB)


  1. Abdel-Salam GM, Abdel-Hamid MS, Issa M, Magdy A, El-Kotoury A, Amr K (2012) Expanding the phenotypic and mutational spectrum in microcephalic osteodysplastic primordial dwarfism type I. Am J Med Genet A 158(6):1455–1461CrossRefGoogle Scholar
  2. Abdel-Salam GM, Abdel-Hamid MS, Hassan NA, Issa MY, Effat L, Ismail S, Aglan MS, Zaki MS (2013) Further delineation of the clinical spectrum in RNU4ATAC related microcephalic osteodysplastic primordial dwarfism type I. Am J Med Genet A 161(8):1875–1881CrossRefGoogle Scholar
  3. Brunetti-Pierri N, De Brasi D, Ikegawa S, Camera G, Andria G, Sebastio G (2003) A new patient with Lowry–Wood syndrome with mild phenotype. Am J Med Genet A 118(1):68–70CrossRefGoogle Scholar
  4. Dayem Ullah AZ, Lemoine NR, Chelala C (2013) A practical guide for the functional annotation of genetic variations using SNPnexus. Brief Bioinform 14(4):437–447CrossRefGoogle Scholar
  5. Edery P, Marcaillou C, Sahbatou M, Labalme A, Chastang J, Touraine R, Tubacher E, Senni F, Bober MB, Nampoothiri S et al (2011) Association of TALS developmental disorder with defect in minor splicing component U4atac snRNA. Science 332(6026):240–243CrossRefGoogle Scholar
  6. Farach LS, Little ME, Duker AL, Logan CV, Jackson A, Hecht JT, Bober M (2018) The expanding phenotype of RNU4ATAC pathogenic variants to Lowry Wood syndrome. Am J Med Genet A 176(2):465–469CrossRefGoogle Scholar
  7. Gulko B, Hubisz MJ, Gronau I, Siepel A (2015) A method for calculating probabilities of fitness consequences for point mutations across the human genome. Nat Genet 47(3):276–283CrossRefGoogle Scholar
  8. Haan EA, Furness ME, Knowles S, Morris LL, Scott G, Svigos JM, Vigneswaren R (1989) Osteodysplastic primordial dwarfism: report of a further case with manifestations similar to those of types I and III. Am J Med Genet 33(2):224–227CrossRefGoogle Scholar
  9. Hankenson LG, Ozonoff MB, Cassidy SB (1989) Epiphyseal dysplasia with coxa vara, microcephaly, and normal intelligence in sibs: expanded spectrum of Lowry–Wood syndrome? Am J Med Genet 33(3):336–340CrossRefGoogle Scholar
  10. He H, Liyanarachchi S, Akagi K, Nagy R, Li J, Dietrich RC, Li W, Sebastian N, Wen B, Xin B et al (2011) Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I. Science 332(6026):238–240CrossRefGoogle Scholar
  11. Kilic E, Yigit G, Utine GE, Wollnik B, Mihci E, Nur BG, Boduroglu K (2015) A novel mutation in RNU4ATAC in a patient with microcephalic osteodysplastic primordial dwarfism type I. Am J Med Genet A 167(4):919–921CrossRefGoogle Scholar
  12. Lowry RB, Wood BJ (1975) Syndrome of epiphyseal dysplasia, short stature, microcephaly and nystagmus. Clin Genet 8(4):269–274CrossRefGoogle Scholar
  13. Lowry RB, Wood BJ, Cox TA, Hayden MR (1989) Epiphyseal dysplasia, microcephaly, nystagmus, and retinitis pigmentosa. Am J Med Genet 33(3):341–345CrossRefGoogle Scholar
  14. Magnani C, Tedesco SA, Dallaglio S, Sommi M, Bacchini E, Vetro A, Zuffardi O, Bevilacqua G (2009) Multiple joint dislocations: an additional skeletal finding in Lowry–Wood syndrome? Am J Med Genet A 149(4):737–741CrossRefGoogle Scholar
  15. Majewski F, Spranger J (1976) A new (brachymelic) type of primordial dwarfism (author’s transl). Monatsschr Kinderheilkd 124(6):499–503PubMedGoogle Scholar
  16. Meinecke P, Schaefer E, Wiedemann HR (1991) Microcephalic osteodysplastic primordial dwarfism: further evidence for identity of the so-called types I and III. Am J Med Genet 39(2):232–236CrossRefGoogle Scholar
  17. Merico D, Roifman M, Braunschweig U, Yuen RK, Alexandrova R, Bates A, Reid B, Nalpathamkalam T, Wang Z, Thiruvahindrapuram B and others (2015) Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing. Nat Commun 6:8718CrossRefGoogle Scholar
  18. Nevin NC, Thomas PS, Hutchinson J (1986) Syndrome of short stature, microcephaly, mental retardation, and multiple epiphyseal dysplasia—Lowry–Wood syndrome. Am J Med Genet 24(1):33–39CrossRefGoogle Scholar
  19. Pierce MJ, Morse RP (2012) The neurologic findings in Taybi–Linder syndrome (MOPD I/III): case report and review of the literature. Am J Med Genet A 158(3):606–610CrossRefGoogle Scholar
  20. Pollard KS, Hubisz MJ, Rosenbloom KR, Siepel A (2010) Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res 20(1):110–121CrossRefGoogle Scholar
  21. Putoux A, Alqahtani A, Pinson L, Paulussen AD, Michel J, Besson A, Mazoyer S, Borg I, Nampoothiri S, Vasiljevic A et al (2016) Refining the phenotypical and mutational spectrum of Taybi–Linder syndrome. Clin Genet 90(6):550–555CrossRefGoogle Scholar
  22. Roifman CM (1999) Antibody deficiency, growth retardation, spondyloepiphyseal dysplasia and retinal dystrophy: a novel syndrome. Clin Genet 55(2):103–109CrossRefGoogle Scholar
  23. Turunen JJ, Niemela EH, Verma B, Frilander MJ (2013) The significant other: splicing by the minor spliceosome. Wiley Interdiscip Rev RNA 4(1):61–76CrossRefGoogle Scholar
  24. Verma B, Akinyi MV, Norppa AJ, Frilander MJ (2018) Minor spliceosome and disease. Semin Cell Dev Biol 79:103–112CrossRefGoogle Scholar
  25. Yamamoto T, Tohyama J, Koeda T, Maegaki Y, Takahashi Y (1995) Multiple epiphyseal dysplasia with small head, congenital nystagmus, hypoplasia of corpus callosum, and leukonychia totalis: a variant of Lowry–Wood syndrome? Am J Med Genet 56(1):6–9CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Divisions of Medical Genetics, Department of PediatricsCHU Sainte-Justine, Université de MontréalMontrealCanada
  2. 2.CHU Sainte-Justine Research CenterMontrealCanada
  3. 3.Neonatology and Neonatal Intensive Care Unit, Maternal and Child DepartmentUniversity of ParmaParmaItaly
  4. 4.Clinical Genetics DepartmentGuy’s Hospital, Guy’s and St Thomas’ NHS Foundation TrustLondonUK
  5. 5.Laboratory of Human GeneticsGalliera HospitalGenoaItaly
  6. 6.Telethon Institute of Genetics and MedicinePozzuoliItaly
  7. 7.Department of Translational MedicineFederico II University of NaplesNaplesItaly

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